Despite decades of intense global research, initiatives to slow the clinical progression of AD have largely failed. This is attributable not only to the complexity inherent to AD, but also to the fact that AD is believed to be the result of myriad chronic, and perhaps even lifelong, physiological and genetic alterations that may not be immediately reversible. To evaluate the potential for early intervention for AD in pre-clinical populations, "lifestyle factors" known to increase the risk of cardiovascular diseases (cardiovascular risk factors (CvRFs)), have recently been evaluated as potential risk factors of AD. For example, recent evidence indicates that late life insulin resistance (a feature of non-insulin dependent diabetes mellitus), known to increase the risk of cardiovascular disease, increases the risk of AD dementia by >2-4 fold. Additionally, recent studies have reported decreased insulin insensitivity in the AD brain, and shown that insulin-sensitizing drugs in AD can improve cognition. To identify biological markers of the CvRF insulin resistance, and to further explore the relationship of insulin resistance to AD and early pre-clinical AD, we have studied insulin resistance in vivo using as experimental diabetogenic mouse model. Encouragingly, in recent high throughput genomic studies we identified several families of genes whose expression were altered under conditions of diabetogenic diet induced insulin resistance, and found these genes to be comparably regulated in the AD brain as a function of the clinical progression of AD dementia. This novel discovery provides a critical biological link between AD and insulin resistance, and supports further study of insulin resistance in the context of AD etiology. Further, in preliminary studies using a transgenic mouse model of AD, we found that diet induced insulin resistance significantly promoted beta-amyloid peptide generation in the brain of a transgenic mouse model of AD (Tg 2576 mice). In this application we propose to continue to investigate the regulation of these novel biomarker gene products of "insulin resistance" in AD and in AD model systems, and explore their specific relationship to AD-type neuropathology and cognition. At the completion of the funding period it is expected that we will develop an understanding of the biological relationship of insulin resistance to AD, yield feasibility data for ongoing and future anti-diabetic drug clinical trials in AD, and generate biological criteria for diagnosing/monitoring this CvRF in AD dementia and populations at high-risk of AD.